Osteolytic bone metastasis is a prominent feature of many cancers including those of the breast, prostate, thyroid and lung. These metastases drive excessive bone resorption by increasing osteoclast activity and differentiation. Recent work has shown that the RANKL/RANK pathway is critical to osteoclast development, and that RANK is necessary for the formation of osteolytic bone metastasis. Work from my group reveals an alternate arm of the RANK/RANKL pathway controlled by the NF-kappaB inducing kinase (NIK). Although NIK deficient mice exhibit normal osteoclast number, bone architecture and bone development, they fail to develop an osteoclastogenic response when injected with RANKL or PTH, which acts by upregulating RANKL. Moreover, osteoclast precursors from NIK-/- mice fail to develop osteoclasts in response to RANKL, in vitro. In contrast however, progenitors from NIK-/- mice can form osteoclasts, in vitro, when presented with TNFalpha and/or TGFbeta. The broad objectives of this study are to define the NIK dependent path to osteoclast differentiation, and to determine if proteins involved in this pathway (including NIK) are relevant therapeutic targets for bone metastasis. We hypothesize that: 1. Networks of genes controlled by RANKL during osteoclastogenesis are perturbed in NIK-/- cultures, and normalized by TGFbeta/TNFalpha treatment. 2. NIK-/- mice are protected from osteolytic bone metastases. Our specific aims are therefore to: 1. Use gene expression profiling to define networks of genes controlled by RANKL during osteoclastogenesis that are perturbed in NIK-/- cultures, and restored by TGFbeta/TNFalpha treatment. 2. Determine whether or not NIK-/- mice are protected from bone lesions in multiple forms of osteolytic bone metastasis.